Resorbable matrices with coatings for delivery of bioactive compounds

ABSTRACT

This invention relates to the production and use of coated inorganic-biopolymer complexes for the controlled release of bioactive compounds including medicinals. Advantageously, the delivery system compositions include an inorganic, a matrix polymer, and a coating. Advantageously, the inorganic used is calcium sulfate.

FIELD OF THE INVENTION

This invention relates generally to the production and use ofinorganic-polymer matrices with coatings. The matrices and coatings areresorbable. Sustained and/or controlled release of medicinal agents andother bioactive substances are the primary uses of these systems.

BACKGROUND OF THE INVENTION

Plaster of Paris (POP) has been used without matrix biopolymers ormedicinal complexing agents as CaSO₄-1/2H₂O [D. Mackey, et al, Clin.Orthop., 167, 263 (1982); and G. W. Bowyer, et al, J. Trauma, 36, 331(1994)]. Polymethylmethacrylate and POP have been compared with regardto release profiles. Release rates from POP tend to be very fast.

Both polymethylmethacrylate and POP can be used to produce dimensionallystable beads and other structures. The acrylate cements or beads areformed by mixing pre-formed polymethylmethacrylate polymer,methylmethacrylate monomer, and a free-radical initiator.

An exothermic reaction ensues which results in matrix temperatures ashigh as 100° C. Many antibiotics such as polymyxin and tetracycline areinactivated by these conditions [G. J. Popham, et al, Orth. Rev., 20,331 (1991)]. As mentioned above, polymethylmethacrylate is biocompatiblebut not resorbable. Therefore, beads used to treat local infection mustbe retrieved by surgery which is accompanied by the risk ofre-infection. POP beads or pellets are resorbable but show inferior drugrelease profiles [G. W. Bowyer, et al, J. Trauma, 36, 331 (1994)].

Polymer matrices designed for controlled release of bioactive compoundscan be non-resorbable or resorbable. In general, resorbable meansdegradable in the body by erosion from the surface or breakdown fromwithin. The mechanism can involve either a chemical reaction, such ashydrolysis, or dissolution.

Non-resorbable polymers, such as polymethylmethacrylate, have been usedfor antibiotic delivery. These materials suffer from the disadvantagethat they must be retrieved, which involves a second intervention andentails the risk of infection (H W Bucholz, et al., (1970) Chiburg, 43,446).

Resorbable polymer matrices for controlled release are usually based onan oxygen-containing monomer, which is condensed in organic solvent toyield the polymeric product. The bioactive agent and the polymer arethen combined in such a way as to give a timed-release formulation. Thecombination of active ingredient and polymer often involves organicsolvents as well. The use of organic solvents is a decided disadvantage,especially when large-scale production is required. Toxic residues oforganic solvents are a concern. Proteins and many polypeptides areincompatible with organic solvents.

The types of polymers in this category include:

-   -   polyesters    -   polyanhydrides    -   polyketals    -   poly(orthoesters)    -   polyurethanes        (Burkersroda, F V and Goepferich, A M in Biomedical Materials, T        Neenan, M Marcolongo and R F Valentini, eds. (1999), page 23,        Materials Research Society, Warrendale Pa.).

Naturally occurring proteins may be used as structural components indrug-delivery matrices (Royer, U.S. Pat. No. 4,349,530; Royer, U.S. Pat.No. 5,783,214; Lee, Science (1981) 233-235). One deficiency ofproteinaceous delivery matrices is that they can exhibit instabilityespecially in environments where an inflammatory reaction is presentsuch as a site of localized sepsis.

Commonly owned WO 99/15150 and U.S. Pat. No. 6,391,336 disclose stable,yet practical compositions for use in inflamed sites comprising aninorganic compound, a matrix polymer and/or a complexing agent. Thiscomposition has the advantage of being biocompatible but, unlikesynthetic organic polymers, no non-aqueous solvents are required in thepreparation. The drug is incorporated as a solid or as part of thematrix polymer solution. The material can also be used as a cement, thatis, it can be injected directly into a lesion and allowed to solidify insitu.

Commonly owned U.S. Ser. No. 09/703,710 discloses a delivery system witha conditioning agent.

OBJECTS OF THE INVENTION

It is an object of this invention to provide a safe resorbable deliverysystem that can be designed and fashioned to provide controlled releaseof bioactive substances over a pre-determined time-course.

It is an object of this invention to improve control of medicinalrelease rate and residence time.

SUMMARY OF THE INVENTION

The subject invention relates to compositions for the controlled releaseof an active agent comprising an active agent and a matrix polymerdispersed throughout a matrix having a coating wherein said matrix isthe hydration reaction product of an aqueous mixture comprised of:

-   -   an inorganic compound capable of undergoing hydration and/or        crystallization, and    -   a matrix polymer,    -   wherein the inorganic compound of the matrix becomes a solid by        hydration and/or crystallization.

Included within the invention are methods of producing the compositionsand methods of producing sustained release of medicinals in mammals byadministering the delivery systems with medicinals to mammals.

DETAILED DESCRIPTION OF THE INVENTION

Introduction

The subject invention relates to a resorbable matrix with advantageous,i.e. sustained or controlled, release kinetics. The matrices are capableof releasing an active agent for a few days, e.g., 1, 2 or 3 days, 1, 2,or 3 weeks, or as many as 6 weeks. Inorganic compounds such asCaSO₄-1/2H₂O (calcium sulfate hemihydrate) can be combined withbiopolymer in the presence of a bioactive agent including medicinals toproduce a matrix, which is subsequently coated. Optionally, included area complexing agent and a conditioning agent.

As used herein, the term “matrix polymer” refers to a polymer (often abiopolymer), which serves to control the erosion rate, setting time, andinfluences the release profile by raising the viscosity of the medium inthe pores and channels of the delivery system. A “biopolymer” is definedas a pharmacologically acceptable polymer of biological or syntheticorigin.

As used herein, the term “complexing agent,” refers to an agent (often abiopolymer), which is used to form a salt or conjugate with the activeagent, which in effect raises the molecular weight of the active agentand lowers its rate of efflux. The complexing agent is typically a smallmolecule, which has affinity for the active agent. Pharmacologicallyacceptable hydrophobic medicinal complexing agents include proteins suchas albumin, lipids or cyclodextrins, which can be used to complexneutral medicinal molecules or charged molecules, which contain ahydrophobic moiety. Liposomes containing a medicinal can be entrappedwithin the calcium sulfate matrix.

The delivery system of the subject invention for use with medicinalsmust meet the following requirements:

-   -   1. Safety—non-toxic, non-immunogenic, non-pyrogenic,        non-allergenic.    -   2. Resorbablility—all components should be either assimilable or        readily excreted.    -   3. Stability—the matrix should be sterilizable and precursors        should have an acceptable shelf life. Cast forms should be        dimensionally stable.    -   4. Compatibility—the materials and the preparative conditions        should not alter the chemistry or activity of the medicinal.    -   5. Programmability—the residence time and release profile should        be adjustable.

The inorganic compound-conditioning agent composites described hereinare resorbable by dissolution. No acid is produced as opposed tohydrolytic erosion of polymer matrices such as polyesters.

Entrapment of bioactive substances within the resorbable biocompatiblematrix described herein yields a delivery system, which permitscontrolled and localized release of a bioactive agent. Inorganiccompounds such as CaSO₄-1/2H₂O can be combined with a polymer in thepresence of a bioactive agent to produce a solid, which constitutes abiocompatible and resorbable delivery matrix (See WO 99/15150 and U.S.Pat. No. 6,391,336 the entire contents of which are incorporated byreference herein). The matrix is then coated.

Matrix Production

The production of the delivery system can be illustrated as follows:

When contacted with water, calcium sulfate hemihydrate is converted tothe dihydrate, CaSO, 2H₂O, which crystallizes. The mass of interlockingneedle-like crystals produces a porous matrix with high compressivestrength, as much as 2000 psi or more.

The slurry can be injected into molds to form spheres, cylinders, etc,or it can be allowed to solidify in bulk. In the latter case, the solidis milled and sized to yield microgranules. These microgranules can thenbe suspended in solution and injected. Microgranules can also be used inoral dosage forms.

A conditioning agent such as calcium stearate can be pre-mixed with thecalcium sulfate hemihydrate. The slurry can be injected into the desiredlocation with solidification in situ.

This composition is ideal for dental and orthopedic applications. Thefact that the slurry can set-up in the presence of moisture is veryadvantageous.

The matrix is formed by the following reaction:

Normally, 1 g of calcium sulfate hemihydrate is treated with 0.6 ml ofaqueous solution containing the matrix polymer along with dissolved ordispersed drug. The drug can also be incorporated into the formulationas a solid, ground with the calcium sulfate hemihydrate.

This formulation produces a hard porous mass of interlocking spheruliticcrystals.

The inorganic-biopolymer complex can be formed as spheres, granules,cylinders, tablets and beads (including microbeads) for injection or foruse in capsules. The latter can be formed by dispersing the slurry intoa rapidly stirring water-immiscible medium. The size of the beads can bedetermined by the amount and nature of the surfactant and the stirringrate. Milling and sieving to produce beads/granules is an alternativeapproach. For orthopedic and dental use the inorganic-biopolymer complexmatrix can be molded and or carved into specific shapes to conform tovoids in bone structures. Just prior to formation of the intractablesolid, the material is plastic and can be conveniently shaped to fitopenings of irregular geometry.

Production of Dosage Forms

A delivery matrix of the invention can be produced by:

-   -   a. blending of an inorganic such as calcium sulfate hemihydrate        and a conditioning agent such as calcium stearate, both in        powder form,    -   b. mixing with matrix polymer solution (the drug can be        dissolved or suspended in the polymer solution),    -   c. solidification in a mold or in bulk, and    -   d. unmolding or preparing microgranules by milling and sizing.

The molds, made of stainless steel or Teflon, can be used to preparecylinders or spheres (e.g., both 3 mm in diameter). The preparation ofwafers is also possible. Microgranules can in turn be compressed intotablets with various binding agents to yield another dosage form.

Surface coating with an erodible substance will block pores and slowefflux of drug until the coating agent is hydrolyzed or dissolved. It ispossible to produce delayed release. Other embodiments include 2, 3 ormore coatings and coatings with varying concentrations of coatingpolymer.

The delivery system typically has the following components:

1. Inorganic Compounds

Calcium sulfate hemihydrate is an advantageous inorganic component. Thehemihydrate takes up water and crystallizes as the higher hydrate.Unadulterated calcium sulfate matrix exhibits poor drug releaseprofiles. With conditioning agents, and optionally matrix polymers andcomplexing agent-active agent complexes the release profiles areimproved. Other inorganics can be employed such as calcium silicates,aluminates, hydroxides and/or phosphates (see pages 72, 95, 327 inReference Book of Inorganic Chemistry (1951) Latimer, W. H., andHildebrand, J. M., Macmillan, New York, hereby incorporated by referencein its entirety).

2. Matrix Polymers

The preferred matrix polymers for medical use are biocompatible(non-toxic, non-allergenic, non-immunogenic), water soluble, andcompatible with other components in the formulation.

Examples of matrix polymers include chondroitin sulfate, dextran(1-50%), hyaluronic acid (e.g., 1-5%), dextran sulfate, pentosanpolysulfate, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP),proteins such as collagen (gelatin), and fibrinogen. In an advantageousembodiment, a crosslinking agent is added to the matrix polymer. Theaddition of the crosslinking agent causes a reaction which leads to ahigher molecular weight matrix polymer which increases viscosity in thepores. Diffusion is thereby inhibited. See Royer U.S. Pat. No. 6,391,336and WO 99/15150, each being hereby incorporated by reference in itsentirety. Counterions, are advantageously sodium or calcium. Chitosan aswell as cationic polypeptides, polylysine, and polyarginine are examplesof useful polymers that are positively charged at neutral pH.

The function of the matrix polymer is to control the viscosity, which isdependent on the nature, molecular weight and concentration of thepolymer. The rationale for using polymers and polymeric complexingagents is based on Stokes law:

-   -   D is proportional to 1/Mv

-   D=the diffusion coefficient

-   M=the molecular weight of the medicinal

-   v=the viscosity of the medium    3. Conditioning Agents

Conditioning agents are used to slow the erosion rate and permitsolidification in the presence of moisture (repels water). Commonlyowned U.S. Ser. No. 09/703,710, hereby incorporated by reference,discloses delivery systems with a conditioning agent.

All conditioning agents have a hydrophobic moiety. Calcium stearate isan advantageous choice for a conditioning agent that meets the criteriaof safety and efficacy. Other calcium salts are useful in this regard.Examples include saturated and unsaturated carboxylic acids, aromaticcarboxylic acids, corresponding phosphates, phosphonates, sulfates,sulfonates, and other compounds containing a hydrophobic moiety with anegatively charged anion. Salts of undecylenic acid are useful, in thatthey provide stability and also antifungal action. The use of calcium asthe cation is advantageous but other cations will suffice; the groupincludes, but is not limited to, zinc, magnesium, aluminum andmanganese.

The generalized chemical structure can be illustrated as follows:R—X-Mwhere R is alkyl, alkenyl, alkynyl or aryl,where X is a carboxylate, a carboxylic acid, an aromatic carboxylicacid, a corresponding phosphate, a phosphonate, a sulfate, or asulfonate, andwhere M is a metal ion such as calcium, zinc, magnesium, aluminum ormanganese.

An example is calcium stearate, (CH₃ [CH₂]₁₆COO—)₂Ca²⁺

In this case R═CH₃[CH₂]₁₆, X═COO—, and M is the metal ion Ca²⁺. Cationicconditioning agents can also be employed, i.e.,R—P—Ywhere R=alkyl, alkenyl, alkynyl or aryl, where P=ammonium, or alkylammonium, and where Y=sulfate or phosphate.4. Complexing Agents

To the extent that polymeric complexing agents increase the effectivemolecular weight of the active ingredient, the rate of efflux is slowedaccording to D is proportional to 1/Mv.

Complexing agents can be polymers or small molecules. The agents canform ionic bridges or hydrophobic bonds with the molecule to bedelivered. The complexes involving the bioactive agents can range fromsparingly soluble to soluble. Disodium pamoate is a good example of acomplexing agent that forms sparingly soluble adducts with cationicbioactive ingredients. Disodium methylene disalicylate is a similarmolecule to disodium pamoate that performs the same function. Procaineand benzathin can be used to reduce the solubility and rate of efflux ofanionic bioactive agents. Additional complexing agents are presented inWO 99/15150.

5. Coatings

Substances useful as coatings which extend residence time, include i)biodegradable poorly water soluble or water insoluble materials suitablefor blocking channels such as fibrin, polylactic acid (PLA),poly(lactide-co-glycolide) (PLGA), polycaprolactone (PCL), waterinsoluble small molecules such as triphenylphosphate and sucroseocta-acetate and acyl glycerols such as glyceryl tristearate or ii)biodegradable viscous water soluble agents such as hyaluronic acid,dextran, dextran sulfate (>100,000 MW), hydroxypropyl methyl cellulose,USP (EPMC), chitosan, and chondroitin sulfate.

The rate of dissolution of the coating influences the release profile.

A. Fibrin Coating

In order to coat the matrix with fibrin, drug is entrapped as usual bymixing calcium sulfate-hemihydrate with matrix polymer solution andallowing the mixture to set. The product is unmolded or processed asusual to microgranules. Water in external pores/channels is removed bydrying overnight at room temperature.

The microbeads are wetted with fibrinogen solution (10% in Hepesbuffer/30 mM, pH 7.2). The ratio of liquid to solid is balanced so thatno excess solution exists in this particular example. When the solutionvolume exceeds the solid volume, the beads are dried to a “damp” stateby removing excess polymer solution. This step can be done on a sinteredglass filter under reduced pressure. Beads tend to stick together andare remilled to get a microbead preparation with the normal consistency.

The number of coating layers allows for control over the releaseprofile. In the body fibrinogen is converted to fibrin. The stability ofthe fibrin layer can be adjusted by added fibrinoligase, the naturallyoccurring enzyme that catalyzes the cross-linking of fibrin clots.

Also, the inclusion of fibrinolysis inhibitors such as aprotinin ande-aminocaproate will slow down the degradation of the coating in vivo.

In another embodiment, the fibrinogen coating solution is diluted withwater or another protein such as collagen or gelatin to change theeffect of the coating.

The use of multiple coating layers and different additives allowspreparation of a series of batches with different release profiles. Thecombination of fast-release, medium-release, and slow-release versionsin varying proportions gives a resultant release profile, which can betailored to the therapeutic requirement. It is possible to generate veryclose to a zero-order release. A final burst can also be obtained.

B. Organic Polymer Coating

1. Microgranules

This process of coating matrices for delivery of protein and non-proteinactive agents involves the following steps:

-   -   removing water from the matrix,    -   soaking of the matrix with polymeric coating solution-polymer in        non-aqueous water miscible solvent such as NMP (N-methyl        2-pyrrolidinone), DMF (dimethylformamide) or THF        (tetrahydrofuran),    -   removing trapped air, typically under reduced pressure,    -   solvent evaporation or exchange.

Optionally, the second step is to pretreat the porous matrix withsolvent prior to soaking the matrix to enhance penetration by thecoating solution. In some instances multiple coatings are desirable.

The use of multiple coating layers and different additives such aspolysorb 80 or a second coating agent e.g. glyceryl tristearate allowspreparation of a series of batches with different release profiles. Thecombination of fast-release, medium-release, and slow-release versionsin varying proportions gives a resultant release profile, which can betailored to the therapeutic requirement. Near zero-order release can beobtained.

In another embodiment, the polymeric coating solution contains drug,which provides additional loading.

The nature and amount of matrix polymer, the relative proportions ofcalcium sulfate hemihydrate and liquid, the complexing agent, and thenature and amount of the conditioning agent permit the adjustment of therelease profile and residence time of the matrix.

2. Films/Fibers Containing Microgranules.

Homogeneous dispersions of matrix microgranules in a coating polymer canbe spread onto glass plates to form films. These films can be useful fortopical and transdermal drug delivery.

Use of NMP (N-methyl 2-pyrrolidinone)-microgranule-PLA mixtures can beused to make films of varying thickness. Injection into CaCl₂ solutionwill also yield “string” or fiber containing matrix microgranules. Thecharacteristics of these fibers are dependent on the concentration oforganic polymer, the medium into which it is injected and the stirringrate.

C. Matrix Beads Dispersed in Organic Polymers

In another embodiment, the matrix beads (or other shapes) are dispersedin the coating material (optionally including the active agent), andformed into cylinders and other various shapes.

Where the coating is a polymer with a melting point 40 C or above suchas polycaprolactone (PCL), then a non-ionic surfactant such aspolyoxyethylenesorbitan monooleate, (Tween 80, Polysorb 80, Span 80,Brij) can be added. The non-ionic surfactant can be adjusted as a meansto regulate the release rate. This is primarily useful for delivery ofnon-protein active agents. This form of the matrix is typically madeinto cylinders, which can be made by molding or extrusion.

In this embodiment, matrix microgranules are typically mixed with moltenorganic polymer melt at >60 C and cooled to yield various shapes. Theorganic polymer is typically water insoluble. Cylinders are anadvantageous form as they can be easily prepared and cut to size.

Polycaprolactone is an example of a bioerodible polymer that is usefulin this application. Other examples are compounds with a melting pointof 40 C and above. As above, free drug as well as drug formulated inmicrogranules can be employed in the dosage form. Additives such asPolysorbate 80 are included to influence the erosion rate and therelease rate.

A representative formulation of a coated matrix follows: IngredientAmount Calcium sulfate hemihydrate 1 g Drug 50 mg Matrix polymersolution (10% w/v) 0.6 ml Calcium stearate 0.1 g Polylactic acid 200 mgWhen the amount of calcium sulfate hemihydrate is set at about 1 g, theamount of bioactive substance is set in the range of 1-300 mg and thematrix biopolymer in the range of 0.4-1 ml.

The concentration of the matrix polymer ranges from 0.1-50% (w/v). Theconditioning agent is present in the range of 5-30% (w/w) based oncalcium sulfate. The ratio of liquid/solid is advantageously 0.6.

The calcium sulfate hemihydrate can be sterilized by dry heat (140 for 4hr); the polymer solution is sterilizable by filtration (0.2-micronfilter). Terminal sterilization by gamma irradiation at 15-18 kGy isalso effective.

A compilation of useful formulations is shown below in Table 1. TABLE 1Representative Coated Dosage Forms Active Dosage Form Ingredient PolymerCoating Microgranules IgG Hyaluronic Acid Microgranules IgG HPMCMicrogranules Growth hormone PLGA Microgranules Growth hormone ChitosanMicrogranules Bupivacaine PLA Microgranules Doxycycline PLA CylindersDoxycycline PCL Cylinders Doxycycline PCL/PS80 Cylinders Gentamicin PCLCylinders Gentamicin/pamoate PCL Cylinders Bupivacaine PCL CylindersBupivacaine PCL/PS80 Film Silver sulfadiazine PLA Film Silversulfadiazine HPMC Film Doxycycline PLA Fibers Doxycycline PLAHPMC = hydroxypropyl methyl cellulose, USPNMP = N-methyl 2-pyrrolidinonePCL = polycaprolactone, MW 10,000PLA = poly (DL-lactic acid), MW 20,000PLGA = poly (L-lactide co-glycolide) 70:30, Polyscience # 16587Uses of the Matrix Compositions of the Invention

Medicinals (both non-protein drugs and medicinal proteins) useful withthe matrices of the invention are presented in commonly owned WO99/15150 and U.S. Ser. No. 09/703,710 each of which is herebyincorporated by reference. Therapeutics, antigens, antibodies includingmonoclonal antibodies, adjuvants, and regulatory molecules such ashormones exemplify bioactive agents with medical applications.

Various anti-infectives useful in conjunction with the formulations ofthe invention include gentamicin, clarithromycin, doxycycline,minocycline and lincomycin, amikacin, penicillin, cefazolin,ciprofloxacin, enrofloxacin, norfloxacin, silver sulfadiazine, imipenem,piperacillin, nafcillin, cephalexin, cefoperazone, vancomycin,tobramycin, nystatin, and amphotericin B or salts thereof (e.g., pamoatesalt). Forming the pamoate (a complexing agent) of these anti-infectivesto form complexes such as amikacin pamoate, clindamycin and gentamicinpamoate, are useful alone or in the formulations of the invention.

Cisplatin, paclitaxel, 5-FU, doxorubicin and other anti-neoplasticagents, can be delivered locally with beads (e.g., 3 mm) or withmicrogranules prepared as described herein. In one embodiment, localizedadministration is beneficial in that systemic toxicity is eliminated butconcentrations in the area of cancerous tissue are high.

Vaccine antigens can be delivered with the system of the invention, forexample, with microgranules (i.m. injection). The system of theinvention can also be used to deliver DNA and RNA antigens.

The delivery system of the invention can also be used to delivernon-medical bioactive agents include sterilants, pheromones, herbicides,pesticides, insecticides, fungicides, algicides, growth regulators,antiparasitics, repellents, and nutrients. (See also WO 99/15150).

Modes of Administration

Administration of the solid matrix can be by surgical implant, oral,i.p., i.a. or p.a. The liquid injection can be s.c., i.m., or i.p.Advantageously, the administration is done by parenteral injection.

1. Slurry

1 g of calcium sulfate/calcium stearate (1-25% w/w) plus amikacinpamoate (100-320 mg) are thoroughly mixed and contacted with 0.6 ml ofaqueous dextran sulfate (10% w/v).

After blending to a smooth slurry (30 s), the material is transferred toa 5 ml syringe and installed in vivo where it solidifies. Amikacinsulfate can be blended with amikacin pamoate to adjust the releaseprofile. Presence of the calcium stearate allows for the solidificationin the presence of moisture.

2. Beads/Cylinders

Sterile 3 mm beads can be installed individually with mosquito forcepsor in groups using a cannula. A teat cannula is a safe tool forinstallation of beads and cylinders. This approach has been successfullyused in the treatment of squamous cell carcinoma via intralesionalchemotherapy with 3 mm beads of the invention containing cisplatin (7%).

3. Microgranules

-   -   a. Injection-Sterile microgranules (45-150 microns) (dry) are        suspended in a suitable liquid for injection just prior to use.        When antibiotics are involved, a solution of the antibiotic of        choice may be used as the suspending liquid. For example, in        treating a septic joint, amikacin solution (3 ml/25%) is used to        suspend microbeads (300 mg) containing amikacin pamoate. An        “initial burst” provided by the soluble amikacin sulfate is        followed by the amikacin that elutes from the microbeads. A        similar approach is appropriate for creating a subcutaneous        depot of antibiotics and other active ingredients.    -   b. Oral-Microgranules are mixed with food or feed. The        composition of the invention is tasteless and in some cases will        mask the taste of a bioactive compound. In addition, the        microgranules of the invention can be included in a capsule for        oral delivery.

The following Examples are illustrative, but not limiting of thecompositions and methods of the present invention. Other suitablemodifications and adaptations of a variety of conditions and parametersnormally encountered which are obvious to those skilled in the art arewithin the spirit and scope of this invention.

EXAMPLES

Matrix Microgranule Formulations of the Examples Matrix FormulationMatrix Polymer CsCast + Active Ingredient I. Azoalbumin 600 ul PEG (5%) 1 g 100 mg azoalbumin II. IgG 400 ul PEG (5%) 670 mg  34 mg IgG  40 mgDS500 (monoclonal antibody) III. Lysozyme 600 ul PEG (5%)  1 g  10 mglysozyme IV. Doxycycline 600 ul PEG (10%)  1 g 160 mg doxycycline-HCL V.Somatotropin 600 ul PEG (5%)  1 g 300 mg somatotropinAbbreviations Used

-   -   CsCast=calcium sulfate/calcium stearate (95/5,wt/wt)    -   PBS=phosphate buffered saline (10 mM phosphate buffer-pH 7.4,        2.7 mM KCl, 13.7 mM NaCl)    -   PEG=polyethyleneglycol, MW 8,000    -   DS500=dextran sulfate MW 500,000    -   HPMC=hydroxypropyl methyl cellulose, USP    -   NMP=N-methyl 2-pyrrolidinone    -   PCL=polycaprolactone, MW 10,000    -   PLA=poly (DL-lactic acid), MW 20,000    -   PLGA=poly (L-lactide co-glycolide) 70:30, Polyscience # 16587

Example 1 Coating of Matrix-Azoalbumin (I) Microgranules withHydroxypropyl Methyl Cellulose (HPMC)

300 mg of azoalbumin microgranules (I) was mixed with 600 mg of 5% HPMC(aq) to obtain a smooth suspension. The product was allowed to dry atroom temperature for 24 hr with protection from light and dust. The drymaterial was milled and resized to 45-150 microns.

Release Profile

50 mg of coated beads was placed in a 2 ml centrifuge tube and overlayedwith 500 μl PBS.

This was incubated at 37 C for 24 hrs and then centrifuged at 13,000 RPMfor 5 minutes. The supernatant was removed and analyzedspectrophotometrically (450 nm). The process was repeated at 24 hrintervals for 4 days. The amount of protein in the eluent was calculatedfrom a standard curve. Release profile (1) Day % Released 1 14.5 2 3.6 33.4 4 4.1

Example 2 Coating of Matrix-Azoalbumin (I) Microgranules with SucroseOcta-acetate

300 mg Matrix-Azoalbumin (I) microgranules was mixed with 200 μl ofsucrose octa-acetate wt/vol in NMP) until all beads were wet.

This was left to dry at room temperature for 24 hours and protected fromlight and dust. The dried material was then milled and resized to obtainparticles 45-150 microns.

Release Profile

50 mg of coated beads was placed in a 2 ml centrifuge tube with 500 μlPBS. This was incubated at 37 C for 24 hrs and then centrifuged at13,000 RPM for 5 minutes. The supernatant was then analyzedspectrophotometrically (450 nm). The process was repeated at 24 hrintervals for 6 days. The amount of protein in the eluate was calculatedfrom a standard curve. Release profile (2) Day % Released 1 1.0 2 0.2 30.1 4 2.1 5 7.8 6 6.2

Example 3 Coating of Matrix-IgG (II) Microgranules with Fibrin

150 mg of Matrix-IgG (II) was mixed with 150 μl of 1% fibrinogensolution (porcine fibrinogen in 30 mM Hepes buffer pH 7.2) to obtain asmooth suspension. This material was then used directly or lyophilized.

Release Profile

The suspension was transferred into a 1 ml syringe and 501 injected intoa 2-ml centrifuge tube. 500 μl PBS was added and the material incubatedat 37 C for 24 hrs and then centrifuged at 13,000 RPM for 5 minutes. Thesupernatant was removed and analyzed spectrophotometrically (280 nm).Eluent from 50 μl blank beads (150 mg Matrix-beads (670 mg 5% CSCast, 40mg dextran sulfate M.W. 500,000) was mixed with 150 μl of 1% fibrinogensolution) and was used as a control to compensate for backgroundabsorbance. The supernatant was removed and analyzed at 24 hr intervalsfor 4 days. The amount of released protein was calculated from astandard curve (A280). Release profile (3) Day % Released 1 25.9 2 6.5 33.8 4 4.5

Example 4 Coating of Matrix-IgG (II) Microgranules with Hyaluronic Acid

150 mg Matrix-IgG (II) microgranules was mixed with 150 mg of 3%hyaluronic acid solution to obtain a smooth suspension. The suspensionwas injected directly or lyophilized as before.

Release Profile

The suspension was transferred into a 1 ml syringe and 50 μl injected toa 2 ml centrifuge tube. 500 μl PBS was added and the material wasincubated at 37 C for 24 hrs. It was then centrifuged at 13,000 RPM for5 minutes. The supernatant was removed and analyzedspectrophotometrically (280 nm). The process was repeated at 24 hrintervals for 6 days. The amount of protein released was calculated froma standard curve (A280). Release profile (4) Day % Released 1 12.3 2 7.73 6.4 4 4.0 5 3.4 6 4.4

Example 5 Coating of Matrix-Lysozyme (III) Microbeads with Poly(L-lactide Co-glycolide) PLGA

300 mg-Lysozyme (III) microgranules was mixed with 300 μl of PLGAsolution (10% wt/vol in NMP). The beaker containing the wet beads wasplaced in a dessicator and a vacuum pulled for 5 minutes. The material(not more than 3 mm thick) was spread on a glass tray protected fromlight and dust and left to dry at room temperature for 48 hours. Thedried material was milled and sized to obtain particles 45-150 microns.

Release Profile

50 mg coated microgranules was placed a 2 ml centrifuge tube and 500 μlPBS was added. This was incubated at 37 C for 24 hrs and thencentrifuged at 13,000 RPM for 5 minutes. The supernatant was removed;and analyzed spectrophotometrically (280 nm). The process was repeatedat 24 hr intervals for 4 days. The amount of released protein wascalculated from a standard curve (A280). Release profile (5) Day %Released 1 18.5 2 5.1 3 4.5 4 3.3

Example 6 Coating of Matrix-Azoalbumin (I) Microgranules with Fibrin

300 mg Matrix-azoalbumin (I) microgranules was mixed with 200 μl of 10%fibrinogen solution (porcine fibrinogen in 30 mM Hepes buffer pH 7.2)and left to dry at room temperature for 24 hours while being protectedfrom light and dust. The material was not sealed. It was then milled andsized to obtain particles of 45-150 microns.

Release Profile

100 mg of coated microgranules was placed in 2 ml centrifuge tube and900 μl PBS plus 100 μl thrombin solution (4.7 units/ml bovine thrombinin 30 mM Hepes pH7.2, 15N NaCl and 25% Glycerol) was added. This wasincubated at 37 C for 24 hrs and then centrifuged at 13,000 RPM for 5minutes. The supernatant was removed from the centrifuge tube; andanalyzed spectrophotometrically (450 nm). The process was repeated at 24hr intervals for 4 days. The amount of released protein was calculatedfrom a standard curve. Release profile (6) Day % Released 1 1.4 2 1.9 31.4 4 1.0

Example 7 Cylinders Containing Matrix Doxycycline (IV) Microgranuleswith Polycaprolactone

1 g PCL (Ave. M.W. 10,000) was placed into a 25 ml beaker and warmed to75 C for 30 minutes or until melted. The temperature was reduced to 65 Cand 1 g of matrix doxycycline microgranules (45-150μ) was added; thematerial was mixed to form a smooth slurry. The material was transferredto a 3 ml syringe with the aid of a spatula. The syringe was warmed to65 C and the contents were injected into a cylindrical mold (ID=3 mm).After a setting time of at least 30 minutes, the cylinders were unmoldedand cut to the desired length.

Release Profile

100 mg cylinder was placed in 2 ml centrifuge tube. 1 ml PBS was addedand the sample was incubated at 37 C for 24 hrs. The supernatant wasremoved, centrifuged at 13,000 rpm for 5 minutes and analyzedspectrophotometrically (351 nm). The process was repeated at 24 hrintervals 4 days. The amount of released drug was calculated from astandard curve (A351). Release profile (7) Day % Released 1 1.1 2 0.5 30.3 4 0.3

Example 8 Cylinders Containing Matrix Doxycycline (IV) Microgranules andPolycaprolactone(PCL)/Polysorbate 80

500 mg polycaprolactone (Ave. M.W. 10,000) was placed into a 25 mlbeaker and warmed to 75 C for 30 minutes or until melted. 500 μl ofPolysorbate 80 was added and the material stirred until homogeneous. Thetemperature was reduced to 65 C and 1 g of matrix doxycyclinemicrogranules (45-150μ) was added and the material was mixed to form asmooth slurry. The material was transferred to a 3 ml syringe with theaid of a spatula. The syringe was warmed to 65 C and the contentsinjected into a cylindrical mold (ID=3 mm). The setting time was 15minutes. The cylinders were unmolded and cut to the desired length.

Release Profile

100 mg cylinder was placed in a centrifuge tube. 1 ml PBS was added andthe material was incubated at 37 C for 24 hrs. The supernatant wasremoved from the centrifuge tube, centrifuged at 13,000 RPM for 5minutes; and analyzed spectrophotometrically (351 nm). The process wasrepeated at 24 hr intervals for 4 days. The amount of released drug wascalculated from a standard curve (A351). Release profile (8) Day %Released 1 12.7 2 6.0 3 3.3 4 2.6

Variation of the amount of Polysorbate 80 can be a useful tool inadjusting the release profile to meet the demands of the therapeuticsituation. This point is illustrated as shown below: % PS80 % Release,Day 1 25% 7.6% 50%  13%

Example 9 Cylinders Containing Matrix Doxycycline (IV) Microgranules andPolycaprolactone (PCL) Containing Doxycycline

1 g PCL was placed into a 25 ml beaker and the material was warmed to 75C for 30 minutes or until melted. The temperature was reduced to 65 Cand 1 g of Matrix Doxycycline microgranules (45-150μ) and 100 mg ofDoxycycline-HCL was added; the material was then mixed to form a smoothslurry. The material was transferred to a 3 ml syringe with the aid of aspatula. The syringe was warmed to 65 C and the contents were injectedinto a cylindrical mold (ID=3 mm). The setting time was 30 minutes. Thecylinders were unmolded and cut to the desired length.

Release Profile

A 100 mg cylinder was placed in a 2 ml centrifuge tube. 1 ml PBS wasadded and the material incubated for 37 C for 24 hrs. The supernatantwas removed and analyzed spectrophotometrically (351 nm). The processwas repeated at 24 hr intervals for 4 days. The amount of released drugwas calculated from a standard curve (A351). Release profile (9) Day %Released 1 2.3 2 0.8 3 0.6 4 0.5

Example 10 Coating of Doxycycline Microgranules (IV) with Poly(DL-lacticacid)PLA Containing Doxycycline

PLA was dissolved in NMP by warning at 60 C (2 g PLA with 2 ml NMP); andthen allowed to cool to room temperature. Doxycycline was added toachieve a concentration of 10% (w/w). 1 g of the PLA/doxycyclinesolution was mixed with 1 g of doxycycline microgranules (IV) to obtaina homogeneous paste.

This paste can be used directly by forming into various shapes andinstalling at a surgical site such as a periodontal defect. The pastecan be warmed and installed by injection. As an alternative the mixturecan be injected into a rapidly stirring aqueous solution to givespherical beads, the size of which is dependent upon stirring rate andthe presence of surfactants.

Another option is a “string” which can be kept as a coil and formedreadily into the desired shape by the health care professional justprior to use. This dosage form is obtained by simply injecting the abovemixture in unstirred water and coiling the “string” onto a glass rod.

Another alternative is to make semi-cylinders using a Teflon mold. Themold has open troughs in the form of semi-cylinders, which are milledsuch that the width at the top is 3 mm. The mold is filled with asyringe and the solvent is removed in vacuo until a dosage form ofdesired consistency is achieved.

Example 11 Films Containing Doxycycline Microgranules (IV) andPoly(DL-lactic acid)PLA

PLA-NMP solution was prepared (23% w/w). 100 mg Doxycyclinemicrogranules (IV) were mixed with the PLA solution (200 μl) to give asmooth slurry. The mixture was spread onto a glass plate and allowed toair dry for 48 hrs while protected from light and dust.

Example 12 Coating of Matrix-Somatotropin (V) withPoly-DL-Lactide-Co-Glycolide (PLGA)

300 mg Matrix-Somatotropin (V) microgranules were placed into a 10 mlbeaker. 300 μl of poly-DL-lactide-co-glycolide solution (5% wt/vol in1-Methyl-2-pyrrolidinone) was added and the material was mixed until allbeads were wet. The beaker containing the wet beads was placed in adessicator and a vacuum pulled for 5 minutes or until no air bubbleswere observed. The material was spread (not more than 3 mm thick) on aglass tray and left to dry at room temperature for 48 hours. The traywas covered lightly to protect from dust. It was not sealed. The drymaterial was milled using a mortar and pestle; and sized to obtainparticles 45-150 microns.

50 mg coated beads were placed in a 2 ml centrifuge tube with 500 μl PBSbuffer. This mixture was incubated in a water bath at 37° C. for 24 hrs.The supernatant was removed and then centrifuged 13,000 RPM for 5minutes and analyzed spectrophotometrically (280 nm). The process wasrepeated at 24 hr intervals for 5 days. The amount of released proteinwas calculated from a standard curve (A280). Release profile (12) Day %Released 1 4.6 2 0.4 3 1.2 4 2.0 5 2.2

It will be readily apparent to those skilled in the art that numerousmodifications and additions may be made to the present invention, thedisclosed device, and the related system without departing from theinvention disclosed.

1. A composition for the controlled release of an active agentcomprising an active agent and a matrix polymer dispersed throughout amatrix having a coating wherein said matrix is the hydration reactionproduct of an aqueous mixture comprised of: an inorganic compoundcapable of undergoing hydration and/or crystallization, and a matrixpolymer, wherein said inorganic compound of said matrix becomes a solidby hydration and/or crystallization.
 2. A composition as in claim 1,wherein said inorganic compound is calcium sulfate hemihydrate.
 3. Acomposition as in claim 1, wherein said matrix polymer is a biopolymerselected from the group consisting of hyaluronic acid, chondroitinsulfate, dextran, dextran sulfate, and polyethylene glycol.
 4. Acomposition as in claim 3, wherein said matrix polymer is dextransulfate.
 5. A composition as in claim 3, wherein said matrix polymer ispolyethylene glycol.
 6. A composition as in claim 1, further comprisinga conditioning agent.
 7. A composition as in claim 6, wherein saidconditioning agent is selected from the group consisting of calciumstearate, zinc undecylenate, magnesium palmitate, sodium laurate,calcium napthenate, calcium oleate, lauryl and ammonium sulfate.
 8. Acomposition as in claim 6, wherein said conditioning agent is calciumstearate.
 9. A composition as in claim 1, further comprising acomplexing agent.
 10. A composition as in claim 1, further comprising acomplexing agent selected from the group consisting of chondroitinsulfate, polyglutamic acid, polyaspartic acid, pamoic acid,polynucleotides, a cationic polypeptide, cyclodextrin, polyoxyethylenealcohol, ester or ether, and defatted albumin.
 11. A composition as inclaim 1, wherein said coating is a biodegradable poorly water soluble orwater insoluble agent suitable for blocking channels of said matrix. 12.A composition as in claim 11, wherein said coating is selected from thegroup consisting of fibrin, polylactic acid (PLA),poly(lactide-co-glycolide) (PLGA), and polycaprolactone (PCL).
 13. Acomposition as in claim 1, wherein said coating is fibrin.
 14. Acomposition as in claim 11, wherein said coating is selected from thegroup consisting of triphenylphosphate and sucrose octa-acetate andother acyl sugar derivatives, and acyl glycerols such as glyceryltristearate.
 15. A composition as in claim 1, wherein said coating is abiodegradable viscous water soluble agent suitable for blocking channelsof said matrix.
 16. A composition as in claim 15, wherein said coatingis selected from the group consisting of hyaluronic acid, dextran,dextran sulfate (>100,000 MW), HPMC, chitosan, and chondroitin sulfate.17. A composition as in claim 16, wherein said coating is dextran.
 18. Acomposition as in claim 16, wherein said coating is HPMC.
 19. Acomposition as in claim 1, wherein said system is in the form of a bead,a fiber, a wafer, a tablet, a sphere, a granule or a cylinder.
 20. Acomposition as in claim 1, wherein said system is in the form of acylinder and said matrix is dispersed in said coating.
 21. A compositionas in claim 20 wherein said coating is polycaprolactone (PCL).
 22. Acomposition as in claim 21, further comprising a non-ionic surfactant insaid coating.
 23. A composition as in claim 21, further comprisingactive agent in said coating.
 24. A composition as in claim 1,comprising calcium sulfate dihydrate, calcium stearate,glycosaminoglycan, and a coating.
 25. A composition as in claim 24,wherein said glycosaminoglycan is hyaluronic acid or chondroitinsulfate.
 26. A composition as in claim 1, comprising calcium sulfatedihydrate, calcium stearate and hyaluronic acid and fibrin.
 27. Acomposition as in claim 1, wherein said active agent is a medicinal. 28.A composition as in claim 27, wherein said medicinal is a salt.
 29. Acomposition as in claim 27, wherein said medicinal is a protein.
 30. Acomposition as in claim 27, wherein said medicinal is a growth factor.31. A composition as in claim 27, wherein said medicinal is a drugprecursor.
 32. A composition as in claim 27, wherein said medicinal is acytokine or a colony stimulating factor.
 33. A composition as in claim27, wherein said medicinal is an anti-infective selected from the groupconsisting of gentarnicin, clarithromycin, doxycycline, minocycline andlincomycin, amikacin, penicillin, cefazolin, ciprofloxacin,enrofloxacin, norfloxacin, silver sulfadiazine, imipenem, piperacillin,nafcillin, cephalexin, cefoperazone, vancomycin, tobramycin, nystatin,silver sulfadiazine, imipenem, and amphotericin B or salts thereof. 34.A composition as in claim 27, wherein said medicinal is an antibiotic.35. A composition as in claim 27, wherein said medicinal is anantineoplastic agent.
 36. A composition as in claim 27, wherein saidmedicinal is an anesthetic.
 37. A composition as in claim 1, whereinsaid active agent is a non-medicinal compound.
 38. A composition as inclaim 37, wherein said non-medicinal compound is selected from the groupconsisting of a sterilant, a pheromone, a herbicide, a pesticide, aninsecticide, a fungicide, an algicide, a growth regulator, a nematicide,a repellent, and a nutrient.
 39. A method of producing sustained releaseof a medicinal in a mammal comprising administering the composition ofclaim 1 wherein said active agent is a medicinal to said mammal.
 40. Amethod as in claim 39, wherein said administration is by subcutaneousinjection.
 41. A method of treating an infection in a mammal comprisingadministering the composition of claim 1 wherein said active agent is ananti-infective to said mammal.
 42. A method of producing a compositionfor the controlled release of an active agent comprising: (a) mixing anactive agent, an inorganic compound capable of undergoing hydrationand/or crystallization, and a matrix biopolymer, and (b) drying theproduct of step (a) and (c) coating the product of step (b).
 43. Amethod as in claim 42, wherein said inorganic compound, and aconditioning agent are premixed and then added to said matrixbiopolymer.
 44. A method as in claim 42, wherein step (c) comprises i)dispersing the product of step (b) into a molten polymer and ii) moldingthe product of i) into a predetermined shape.